FAUC 213, a highly selective dopamine D4 receptor full antagonist, exhibits atypical antipsychotic properties in behavioural and neurochemical models of schizophrenia

Frank Boeckler, Holger Russig, Weining Zhang, Stefan Löber, John Schetz, Harald Hübner, Boris Ferger, Peter Gmeiner, Joram Feldon

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Rationale: 2-[4-(4-Chlorophenyl)piperazin-1-ylmethyl]pyrazolo[1,5-a] pyridine (FAUC 213) is a highly selective antagonist at the dopamine D 4 receptor subtype. It was designed as a derivative of two partial antagonists and has been proven to be a complete antagonist in mitogenesis assay. Objectives: In the present study, FAUC 213 was examined for antipsychotic properties in animal models of behavioural neurobiology and neurochemistry. Methods: Different concentrations of FAUC 213 were screened for effects on spontaneous, as well as amphetamine-induced, locomotor activity and apomorphine-induced prepulse disruption. The liability of causing extrapyramidal side effects was investigated in models of catalepsy and by high-performance liquid chromatography (HPLC) detection of dopamine turnover in several brain regions. The application schedule was validated, and the bioavailability of the compound determined, by means of a HPLC-pharmacokinetic study. Results: A significant effect in both the reduction of amphetamine-induced locomotor hyperactivity and the restoration of apomorphine-disrupted prepulse inhibition was found at 30 mg/ kg. This dose proved not to be high enough to induce catalepsy or to increase dopamine turnover in the dorsal striatum, nucleus accumbens and medial prefrontal cortex. The selective D4 antagonist FAUC 213, therefore, is not believed to mediate the above-mentioned effects via D2 receptor antagonism, but a partial involvement of 5-HT 2-and α1-receptors cannot be ruled out at present. Conclusions: We have gathered evidence that FAUC 213 exhibits atypical antipsychotic characteristics.

Original languageEnglish
Pages (from-to)7-17
Number of pages11
JournalPsychopharmacology
Volume175
Issue number1
DOIs
StatePublished - 1 Aug 2004

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Dopamine D4 Receptors
Antipsychotic Agents
Schizophrenia
Catalepsy
Apomorphine
Amphetamine
Dopamine
High Pressure Liquid Chromatography
Serotonin 5-HT2 Receptors
Neurochemistry
Dopamine Antagonists
Neurobiology
Nucleus Accumbens
Locomotion
Prefrontal Cortex
Biological Availability
2-(4-(4-chlorophenyl)piperazin-1-ylmethyl)pyrazolo(1,5-a)-pyridine
Appointments and Schedules
Animal Models
Pharmacokinetics

Keywords

  • Atypical antipsychotic
  • Catalepsy
  • Complete antagonist
  • Dopamine D selective
  • Dopamine turnover
  • FAUC 213
  • Locomotor activity
  • Prepulse inhibition

Cite this

Boeckler, Frank ; Russig, Holger ; Zhang, Weining ; Löber, Stefan ; Schetz, John ; Hübner, Harald ; Ferger, Boris ; Gmeiner, Peter ; Feldon, Joram. / FAUC 213, a highly selective dopamine D4 receptor full antagonist, exhibits atypical antipsychotic properties in behavioural and neurochemical models of schizophrenia. In: Psychopharmacology. 2004 ; Vol. 175, No. 1. pp. 7-17.
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FAUC 213, a highly selective dopamine D4 receptor full antagonist, exhibits atypical antipsychotic properties in behavioural and neurochemical models of schizophrenia. / Boeckler, Frank; Russig, Holger; Zhang, Weining; Löber, Stefan; Schetz, John; Hübner, Harald; Ferger, Boris; Gmeiner, Peter; Feldon, Joram.

In: Psychopharmacology, Vol. 175, No. 1, 01.08.2004, p. 7-17.

Research output: Contribution to journalArticle

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T1 - FAUC 213, a highly selective dopamine D4 receptor full antagonist, exhibits atypical antipsychotic properties in behavioural and neurochemical models of schizophrenia

AU - Boeckler, Frank

AU - Russig, Holger

AU - Zhang, Weining

AU - Löber, Stefan

AU - Schetz, John

AU - Hübner, Harald

AU - Ferger, Boris

AU - Gmeiner, Peter

AU - Feldon, Joram

PY - 2004/8/1

Y1 - 2004/8/1

N2 - Rationale: 2-[4-(4-Chlorophenyl)piperazin-1-ylmethyl]pyrazolo[1,5-a] pyridine (FAUC 213) is a highly selective antagonist at the dopamine D 4 receptor subtype. It was designed as a derivative of two partial antagonists and has been proven to be a complete antagonist in mitogenesis assay. Objectives: In the present study, FAUC 213 was examined for antipsychotic properties in animal models of behavioural neurobiology and neurochemistry. Methods: Different concentrations of FAUC 213 were screened for effects on spontaneous, as well as amphetamine-induced, locomotor activity and apomorphine-induced prepulse disruption. The liability of causing extrapyramidal side effects was investigated in models of catalepsy and by high-performance liquid chromatography (HPLC) detection of dopamine turnover in several brain regions. The application schedule was validated, and the bioavailability of the compound determined, by means of a HPLC-pharmacokinetic study. Results: A significant effect in both the reduction of amphetamine-induced locomotor hyperactivity and the restoration of apomorphine-disrupted prepulse inhibition was found at 30 mg/ kg. This dose proved not to be high enough to induce catalepsy or to increase dopamine turnover in the dorsal striatum, nucleus accumbens and medial prefrontal cortex. The selective D4 antagonist FAUC 213, therefore, is not believed to mediate the above-mentioned effects via D2 receptor antagonism, but a partial involvement of 5-HT 2-and α1-receptors cannot be ruled out at present. Conclusions: We have gathered evidence that FAUC 213 exhibits atypical antipsychotic characteristics.

AB - Rationale: 2-[4-(4-Chlorophenyl)piperazin-1-ylmethyl]pyrazolo[1,5-a] pyridine (FAUC 213) is a highly selective antagonist at the dopamine D 4 receptor subtype. It was designed as a derivative of two partial antagonists and has been proven to be a complete antagonist in mitogenesis assay. Objectives: In the present study, FAUC 213 was examined for antipsychotic properties in animal models of behavioural neurobiology and neurochemistry. Methods: Different concentrations of FAUC 213 were screened for effects on spontaneous, as well as amphetamine-induced, locomotor activity and apomorphine-induced prepulse disruption. The liability of causing extrapyramidal side effects was investigated in models of catalepsy and by high-performance liquid chromatography (HPLC) detection of dopamine turnover in several brain regions. The application schedule was validated, and the bioavailability of the compound determined, by means of a HPLC-pharmacokinetic study. Results: A significant effect in both the reduction of amphetamine-induced locomotor hyperactivity and the restoration of apomorphine-disrupted prepulse inhibition was found at 30 mg/ kg. This dose proved not to be high enough to induce catalepsy or to increase dopamine turnover in the dorsal striatum, nucleus accumbens and medial prefrontal cortex. The selective D4 antagonist FAUC 213, therefore, is not believed to mediate the above-mentioned effects via D2 receptor antagonism, but a partial involvement of 5-HT 2-and α1-receptors cannot be ruled out at present. Conclusions: We have gathered evidence that FAUC 213 exhibits atypical antipsychotic characteristics.

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